Novel propenylamine derivatives and process for the production thereof

ABSTRACT

Novel propenylamine derivatives represented by the general formula   WHEREIN R1, R2, X and A are as defined hereinafter, and pharmaceutically acceptable salts thereof, useful as antipsychotic tranquillizing, analgesic, anti-convulsive, antihypertensive and anti-inflammatory agents are disclosed. The propenylamine derivatives of this invention can be prepared by reacting the corresponding propenyl halide with an amine derivative.

United States Patent Maruyama et al. 1 Dec. 2, 1975 NOVEL PROPENYLAMINE DERIVATIVES 3,644,343 2/1972 Manning 260/240 R AND PROCESS FOR THE PRODUCTION 3,712,898 1/1973 Kaiser et a1 260/293.57

THEREOF [75] Inventors: Isamu Maruyama; Masaru Nakao; Primary Examiner-Arthur Demers Kikuo sasajima; lzumi Yanagihara, Attorney, Agent, or Firm-Sughrue, Rothwell, Mion, all of Osaka; Shigeholnaba; Hisao Zinn and Macpeak Yamamoto, both of Hyogo, all of Japan [73] Assignee: Sumitomo Chemical Company, [57] ABSTRACT Osaka Japan Novel propenylatnine derivatives represented by the [22] Filed: July 10, 1974 g neral formula [21] Appl. No.: 487,401

Related US. Application Data [62] Division of Ser. No. 283,025, Aug. 23, 1972, Pat. No.

l X CH CH=CHN {l [30] Foreign Application Priority Data Aug. 26, 1971 Japan 46-65641 R [52] US. Cl 260/240 A; 260/240 R; 260/240 G; 260/268 R; 260/268 PH; 260/293.6; 260/293.66; 260093.84; 260/294.8 C; 260/562 260/562 A; wherein R R X and A are as defined hereinafter, 2150/6137 260/607 2607612 D; 260/613 and pharmaceutically acceptable salts thereof, useful 424/250; 424/267 as anti-psychotic tranquillizing, analgesic, anti- [51] Int. CL: C071) 471/10 convulsive anti-hyperten5ive and anti-inflammatory Field of Search 260/240 A, 2 0 R, 2 agents are disclosed. The propenylamine derivatives of 260/293.66, 294-8 C this invention can.be prepared by reacting the corresponding propenyl halide with an amine derivative. [56] References Cited v UNITED STATES PATENTS Claim, No Drawings 3,629,267 12/1971 Kaiser et al. 260/294.8 C

and a process for preparing the same. More particu- NOVEL PROPENYLAMINE DERIVATIVES AND PROCESS FOR THE PRODUCTION THEREOF This is a division of Ser. No. 283,025, filed Aug. 23, 1972 now Pat. No. 3,840,529.

SUMMARY OF THE INVENTION CHI- N wherein R is a hydrogen atom or a lower alkanoyl group and R is a hydrogen atom, a halogen atomor a lower alkyl group;

wherein R is a hydrogen atom, o r a lower alkanoyl group and R is a hydrogen atom, a halogen atom or a 65 lower alkyl group;

wherein R is a hydrogen atom, a halogen atom, a lower alkyl group or a trifluoromethyl group; and

wherein R is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, and n is 0, l or 2.

-As used herein, the terms lower alkyl", lower alkoxy and lower alkanoyl mean such groups containingfrom one to seven carbon atoms which may be either straight or branched. Thus, the term lower alkyl group includes, for example, methyl, ethyl, n-propyl, isopropyl, iso-butyl, n-hexyl, and the like, the term lower alkoxy group includes methoxy, ethoxy, npropoxy, iso-propoxy andthe like, and the term lower alkanoyl group includes, for example, acetyl, propionyl, and the like. The term halogen atom includes a chlorine, bromine, fluorine or iodine atom.

The process of this invention comprises reacting a propenyl halide represented by the general formula (II) R1 x CH2CH=CHF z (11) R g i wherein R R and 'X- are as defined above, and Z is a halogen atom, preferably, a chlorine, bromine or iodine atom, with an amine derivative of the general formula (III),

......Y......(III) wherein R R X and Z are as defined above.

An object of this invention is therefore to provide novel propenylamine derivatives represented by the general formula (I) and the pharmaceutically acceptable salts thereof which are useful as anti-psychotic, tranquillizing, analgesic, anti-convulsive, antihypertensive and anti-inflammatory agents.

Another object of this invention is to provide a process for preparing the propenylamine derivatives represented by the general formula (I) and the pharmaceutically acceptable salts thereof.

A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingradient, at least one of the compounds represented by the formula (I) and the pharmaceutically acceptable salts thereof.

The reaction of the present invention is carried out at a temperature between C and the boiling point of the solvent used in the absence or presence of an appropriate dehydrohalogenating agent in an inert organic solvent such as benzene, toluene, xylene, dimethylformamide, pyridine, methanol, ethanol, n-propanol, isopropanol, n-butanol and a mixture thereof.

Examples of the dehydrohalogenating agent which can be used include, for example, an alkali metal carbonate such as sodium carbonate and potassium carbonate, an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide, an alkali metal bicarbonate such as sodium bicarbonate and potassium bicarbonate, an alkali metal hydride such as sodium hydride and potassium hydride, an alkyl amine such as trimethyl amine, and the like.

The novel propenylamine derivatives represented by the general formula (I) can form their acid addition salts with a variety of inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, tartaric acid, salicylic acid, p-toluene sulfonic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, malic acid, formic acid, acetic acid and the like.

The representative compounds of this invention which can be prepared according to the above process are as follows:

1-{ l-[3-(p-Fluorophenylthio)-l-propenyl1-4- piperidyl }-2-oxobenzimidazoline, 1-{1-[3-(p-Fluorophenoxy)-l-propenyl]-4-piperidyl}- 2-oxobenzimidazoline, l-Phenyl-8-[3-(p-fluorophenoxy)-1-propenyl1-4-oxo- 1,3,8-triazaspiro[4,5]decane, l-[3-(p-Fluorophenoxy)-l-propenyl]-4-( pchlorophenyl)-4-hydroxypiperidine, l-[3-(p-Fluorophenoxy)-1-propenyl1-4-(mtrifluorophenyl)-4hydroxypiperidine, l-[3-(p-Fluorophenoxy)-l-propenyl]-4-(omethoxyphenyl )piperazine, 1-[3 (p-Fluorophenylthio)-l propenyl1-4-(0- methoxyphenyl )piperazine,

dehydrohalogenating agent Z CH CH :Cii Z oxobenzimidazoline,

l-{1-[3-(p-Nitrophenylthio)-l-propenyl]-4-piperidyl} Z-oxobenzimidazoline,

l-{ l-[3-(p-Aminophenylthio)-l-propenyl1-4- piperidyli-2-oxobenzimidazoline,

1- {l-[3-(p-Acetamidophenylthio)-l-propenyl1-4- pi'peridyl} -2-oxobenzimidazoline.

The novel propenylamine derivatives and their acid addition salts have valuable pharmacological properties, in particular anti-psychotic, tranquillizing, analgesic, anti-convulsive, anti-hypertensive or antiinflammatory activities.

The propenylamine derivatives of this invention can be administered orally as anti-psychotic, tranquillizing, analgesic, anti-convulsive, anti-hypertensive or antiinflammatory agents in the conventional dosage forms such as tablet, capsule, solution, suspension, elixir or the like.

A typical tablet is constituted by from 1 to 20 per cent binder, e.g. tragacanth', from 5 to 20 per cent lubricant, e.g. talcum, magnesium stearate etc.; an average dose of active ingredient; and q.s. 10 per cent of filler, e.g. lactose. The usual oral dosage is 1 to 1000 mg per as daily.

The present invention is further disclosed in the following examples of more preferred embodiments thereof, which are presented for the purpose of illustration and it is not intended to limit the scope of the invention.

EXAMPLE 1 A mixture of 2.23 g of l-(p-fluorophenylthio)-3- chloro-Z-propene, 2.17 g of l-(4-piperidyl)-2- oxobenzimidazoline, 0.52 g of sodium carbonate, and 30 ml. of dimethylformamide was heated at a temperature of -90C for 12 hours. After cooling, the reaction mixture was poured into ml. of water and extracted with benzene. The extract was then evaporated under reduced pressure. The oily residue was dissolved lPhenyl-8-[S-(p-fiuorophenylthio)-1-propenyl]-4- oxo-l,3,8-triazaspiro[4,5ldecane, m.p. l74-176C.

l-[3-(p-Fluorophenylthio)-l-propenyl]-4-(pchlorophenyl)-4-hydroxypiperidine oxalate, l85l86C (decomposed).

While the invention has been described in detail and in terms of specific embodiments thereof, it will be apparent that various changes and modifications can be made therein without departing from the spirit and scope thereof.

What is claimed is:

l. A propenylamine derivative of the formula wherein R, is a hydrogen atom, a halogen atom, a lower alkyl, lower alkoxy, nitro, lower alkanoylamino'or trifluoromethyl group; R is a hydrogen or halogen atom; X is an oxygen atom, a sulfur atom, a sulfinyl or sulfonyl group; R is a hydrogen atom or a lower alkanoyl group and R is a hydro atom, a halogen atom or a lower alkyl group and the pharmaceutically acceptable addition salts thereof. 

1. A PROPENYLAMINE DERIVATIVE OF THE FORMULA 